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Anticoagulation therapy promotes the tumor immune-microenvironment and potentiates the efficacy of immunotherapy by alleviating hypoxia

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Abstract
Purpose: Here, this study verifies that cancer-associated thrombosis (CAT) accelerates hypoxia, which is detrimental to the tumor immune microenvironment by limiting tumor perfusion. Therefore, we designed an oral anticoagulant therapy to improve the immunosuppressive tumor microenvironment and potentiate the efficacy of immunotherapy by alleviating tumor hypoxia.

Experimental design: A novel oral anticoagulant (STP3725) was developed to consistently prevent CAT formation. Tumor perfusion and hypoxia were analyzed with or without treating STP3725 in wild-type and P selectin knockout mice. Immunosuppressive cytokines and cells were analyzed to evaluate the alteration of the tumor microenvironment. Effector lymphocyte infiltration in tumor tissue was assessed by congenic CD45.1 mouse lymphocyte transfer model with or without anticoagulant therapy. Finally, various tumor models including K-Ras mutant spontaneous cancer model were employed to validate the role of the anticoagulation therapy in enhancing the efficacy of immunotherapy.

Results: CAT was demonstrated to be one of the perfusion barriers, which fosters immunosuppressive microenvironment by accelerating tumor hypoxia. Consistent treatment of oral anticoagulation therapy was proved to promote tumor immunity by alleviating hypoxia. Furthermore, this resulted in decrease of both hypoxia-related immunosuppressive cytokines and myeloid-derived suppressor cells while improving the spatial distribution of effector lymphocytes and their activity. The anticancer efficacy of αPD-1 antibody was potentiated by co-treatment with STP3725, also confirmed in various tumor models including the K-Ras mutant mouse model, which is highly thrombotic.

Conclusions: Collectively, these findings establish a rationale for a new and translational combination strategy of oral anticoagulation therapy with immunotherapy, especially for treating highly thrombotic cancers. The combination therapy of anticoagulants with immunotherapies can lead to substantial improvements of current approaches in the clinic.
Author(s)
강창일권세호김경진김상균김상윤김욱일김인산민누리박성진변영로서형석안서현이나경정승우최정욱Taslim A Al-Hilal
Issued Date
2021
Type
Article
Keyword
adjuvantsimmunologicimmunomodulationtumor microenvironment.
DOI
10.1136/jitc-2021-002332
URI
https://oak.ulsan.ac.kr/handle/2021.oak/8378
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_doaj_primary_oai_doaj_org_article_8e479db98ec94911a3fafc994c6e3c18&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,Anticoagulation%20therapy%20promotes%20the%20tumor%20immune-microenvironment%20and%20potentiates%20the%20efficacy%20of%20immunotherapy%20by%20alleviating%20hypoxia&offset=0&pcAvailability=true
Publisher
Journal for ImmunoTherapy of Cancer
Location
영국
Language
한국어
ISSN
2051-1426
Citation Volume
9
Citation Number
8
Citation Start Page
1
Citation End Page
12
Appears in Collections:
Medicine > Medicine
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